Citations

Abstract Objective Autoimmune encephalitis is a cause of brain inflammation characterized by auto‐antibodies, which target cell surface neuronal proteins and lead to neuronal dysfunction. The most common form is associated with auto‐antibodies to leucine‐rich glioma‐inactivated 1 (LGI1) protein, the presentation of which includes frequent focal seizures. The exact cause of these auto‐antibodies remains unknown, but established predispositions include overrepresented human leukocyte antigen ( HLA ) alleles. Yet, these HLA alleles are themselves common in the healthy ancestry‐matched population. One potential etiological hypothesis is that an environmental trigger, such as the gut microbiome, interacts with a genetically predisposed individual. Methods To investigate this, we studied 42 patients with LGI1‐antibody encephalitis (LGI1‐Ab‐E) and 27 familial/environmentally matched controls, and performed metagenomic shotgun sequencing, to describe the compositional and functional differences in the gut microbiome. Results We observed that LGI1‐Ab‐E gut microbiomes exhibited a significant reduction in the ratio of Firmicutes (or Bacillota) and Bacteroidetes phyla, which is associated with the dosage of HLA susceptibility allele count in patients with LGI1‐Ab‐E. Furthermore, we identified differences in functional gene profiles in the gut microbiome that led to a reduction of neuroinflammatory protective short‐chain fatty acids (SCFAs) in LGI1‐Ab‐E patients. Significance Taken together, our results suggest that a compositional shift in the gut microbiome of LGI1‐Ab‐E associates with a neuroinflammatory state, possibly through the reduction of SCFA production. Our study highlights the potential of the gut microbiome to explain some of the complex condition and unravel etiological questions. Validation studies with greater sample sizes are recommended.

Background N-methyl-D-aspartate receptor antibody encephalitis (NMDAR-Ab-E) can have an onset during, after or prior to a pregnancy. In animal models, transplacental NMDAR immunoglobulin G transfer can affect neurodevelopment. In contrast, clinical reports of mothers affected by NMDAR-Ab-E typically are reassuring. We systematically reviewed maternal, infant and childhood clinical data pertaining to NMDAR-Ab-E with an onset before, during or after pregnancy and compared this to our single autoimmune neurology centre experience. Methods After pre-registration on PROSPERO (CRD42023408447), we searched PubMed and Scopus for NMDAR-Ab-E case reports/series with an onset before, during or after pregnancy (last search 19/10/2023). We extracted maternal, neonatal and childhood outcomes using an idealised checklist to derive summary statistics. Results After quality control, we identified 66 pregnancies in 61 women from 48 reports or series. 72% of women recovered with minimal or no neurological deficits, comparable to non-pregnancy-associated NMDAR-Ab-E. Likewise, 80% of pregnancies resulted in live births with a single neonatal death reported. Data on neonatal outcome measures were frequently unreported, and childhood follow-up was provided in only 60%. Our centre’s experience is consistent: 3/4 mothers recovered with no functional deficits and 7/8 children without evidence of compromise at a median follow-up of 2 years. Conclusions Current evidence does not overall suggest unfavourable maternal, fetal or childhood outcomes after NMDAR-Ab-E. However, the available sample is small, predominantly single case reports with modest follow-up, lacks standardisation, and data are often incomplete. Future approaches should address these caveats: developing multi-centre collaboration towards an international registry.

AbstractBackgroundLGI1‐antibody encephalitis (LGI1‐Ab‐E) is a common form of autoimmune encephalitis where most patients demonstrate ‘good’ clinician‐rated outcomes. However, more targeted questionnaires reveal numerous debilitating symptoms for many years. To better quantify these persistent features, we designed the LGI1‐Antibody Encephalitis Rating (LANTERN) scale, a quantified, disease‐specific patient‐reported outcome measure (PROM), adhering to FDA guidelines.MethodsA participant‐driven mixed‐methods approach to develop a clinically valid questionnaire over three stages: (1) Item generation through semi‐structured interviews; (2) Repeated cognitive debriefing rounds to advance comprehensibility, relevance and comprehensiveness; (3) Psychometric survey to condense the most sensitive and valid questions. Analyses incorporated sensitivity testing with multiple internal and external validations.ResultsFrom 73 items across six domains (Stage 1; n = 18), a questionnaire assessing the frequency and severity of 43 symptoms (80 questions), plus nine activities of daily living (ADL), was developed through cognitive debriefing (Stage 2; n = 15). This 89‐question survey was completed (Stage 3; n = 66 patients and 32 relatives) and distilled, using exploratory factor analyses, to a three‐factor symptom‐burden questionnaire comprising 41 questions (19 symptoms and 6 ADL), separated into physical, cognitive/behavioural and ADL domains. These factors demonstrated strong internal reliability (Cronbach alpha: 0.85–0.91), correlations with relative‐completed questionnaires (R = 0.73–0.85; p < 0.001), good‐to‐excellent intraclass re‐testing correlations (0.81–0.98; n = 19) and strong associations with numerous predefined external measures.DiscussionLANTERN represents a PROM for LGI1‐Ab‐E, with initial content, structural and construct validity and test–retest reliability. It can be used as a reliable, tailored, efficient and sensitive method to establish symptom burden in people with LGI1‐Ab‐E, both in clinical practice and trials.

The long‐term clinical outcomes and associated prognostic factors in contactin‐associated protein‐like 2 (CASPR2)‐antibody diseases are unknown. A total of 75 participants with CASPR2 antibodies were longitudinally assessed for disability, quality‐of‐life, and chronic pain. Although most symptoms improved within 6 months of treatment, neuropathic pain and fatigue were the most immunotherapy refractory, and persisted for up to 6 years. Furthermore, these two factors—but not CASPR2 antibody levels or subclasses—independently predicted worse disability and quality‐of‐life at 24 months. Quality‐of‐life varied widely for any given modified Rankin Scale score, indicating a divergence between patient and clinician assessed outcomes. Further work should study the relative importance of these measures, and the immunopathogenesis underlying intractable symptoms. ANN NEUROL 2025;97:521–528

Abstract Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P &lt; 5 × 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.